US5488102A - Polymerisable carbohydrate esters, polymers therefrom and their use - Google Patents

Polymerisable carbohydrate esters, polymers therefrom and their use Download PDF

Info

Publication number
US5488102A
US5488102A US08/256,828 US25682894A US5488102A US 5488102 A US5488102 A US 5488102A US 25682894 A US25682894 A US 25682894A US 5488102 A US5488102 A US 5488102A
Authority
US
United States
Prior art keywords
sub
compound according
alkyl
radical
carbohydrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/256,828
Inventor
Dirk Vetter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocure Inc
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to US08/467,248 priority Critical patent/US5571882A/en
Application granted granted Critical
Publication of US5488102A publication Critical patent/US5488102A/en
Assigned to CIBA-GEIGY CORPORATION reassignment CIBA-GEIGY CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VETTER, DIRK
Assigned to CIBA SPECIALTY CHEMICALS CORPORATION reassignment CIBA SPECIALTY CHEMICALS CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CIBA-GEIGY CORPORATION
Assigned to BIOCURE, INC. reassignment BIOCURE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CIBA SPECIALTY CHEMICALS CORPORATION
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/02—Esters
    • C08B31/04—Esters of organic acids, e.g. alkenyl-succinated starch
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
    • G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
    • G02B1/041—Lenses
    • G02B1/043—Contact lenses

Definitions

  • the invention relates to polymerisable esters of carbohydrates and dicarboxylic acids having an ester group containing radically polymerisable radicals, to homopolymers and copolymers therefrom, to processes for their preparation and to their use.
  • polymerisable groups into carbohydrates such as, for example, cyclodextrins is desirable owing to their properties, especially their high degree of hydrophilicity, their specific complex-forming behaviour and their bioactivity.
  • Acrylate-containing, methacrylate-containing and cinnamoyl-containing cyclodextrins and polymers therefrom have been described, for example, by A. P. Croft et al. in Tetrahedron, Vol. 39, No. 9, pages 1425 to 1427 (1983).
  • the polymerisable groups are regiospecifically bonded in the 2- or 3-positions. They are obtained by the reaction of suitable activated esters, namely nitrophenylcarboxylic acid esters, with a cyclodextrin.
  • WO 91/17255 describes the enzyme-catalysed preparation of polymers from sugars and dicarboxylic acid esters by means of a regioselective diacylation, wherein the sugar radicals are bonded as comonomers in the polymer backbone and, as a consequence, bioactive properties are virtually lost.
  • cyclosaccharides can be monoacylated regioselectively in the 2- or 3-positions or the primary hydroxy group of monomeric, dimeric or linear oligomeric saccharides can be monoacylated regioselectively, by carrying out the acylation with monovinyl or divinyl esters of dicarboxylic acids.
  • monovinyl or divinyl esters of dicarboxylic acids despite the presence of two ester groups of equal reactivity no dimers or polysubstituted products are obtained.
  • Vinyl ester groups can be transesterified with unsaturated alkanols to form other radically polymerisable monomers or can be amidated with unsaturated amines.
  • the invention relates to compounds of formulae I and Ia
  • R is a radically polymerisable hydrocarbon group
  • R 3 is a direct bond, linear or branched C 1 -C 22 alkylene, C 3 -C 8 cycloalkylene or C 6 -C 14 arylene,
  • A is the radical, reduced by a hydroxy group in a 2- or 3-position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
  • a 1 is the radical, reduced by a hydroxymethyl group, of a monomeric or linear or branched oligomeric carbohydrate or of a derivative of such a carbohydrate, and
  • Y is --O--, --NH-- or --N(C 1 -C 6 alkyl)-.
  • R preferably contains from 2 to 12, especially from 2 to 10 and more especially from 2 to 8, carbon atoms.
  • the radical R can contain ethene or ethyne groups as radically polymerisable groups.
  • R may be, for example, alkenyl, alkynyl, vinylphenyl or vinylbenzyl.
  • alkenyl are vinyl, allyl, 1-propen-2-yl, 1-buten-2- or -3- or -4-yl, 2-buten-3-yl, the isomers of pentenyl, hexenyl, octenyl, decenyl and dodecenyl.
  • Vinyl, allyl and 1-propen-2-yl are preferred.
  • R as alkynyl is preferably an alkynylalkyl radical, for example HCC--C m H 2m -- or C 1 -C 9 alkyl-CC--C m H 2m --wherein m is an integer from 1 to 10, preferably from 1 to 6 and especially from 1 to 4, and the total number of carbon atoms is from 3 to 12, preferably from 3 to 8 and especially from 3 to 6.
  • alkynyl examples are propargyl, 1-butyn-3- or -4-yl, 1-pentyn-3- or -4- or -5-yl, 2-pentyn-4- or -5-yl, 1-hexyn-3- or -4- or -5- or -6-yl, 2-hexyn-4- or -5- or -6-yl, and 3-hexyn-5- or -6-yl.
  • the group Y is preferably --O--, --NH--, --Nmethyl-- or --Nethyl-- and especially --O-- or --NH--.
  • R 3 as alkylene preferably contains from 2 to 20 and especially from 4 to 18 carbon atoms.
  • Some examples are methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, 1,1-, 2,2- or 3,3-pentylidene or 1,1-, 2,2- or 3,3-hexylidene, 1,2-ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3-, 2,3- or 1,4-butylene, 1,2-, 1,3-, 1,4-, 1,5-, 2,3-, 2,4- or 2,5-pentylene, 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 2,3-, 2,4 -, 2,5- or 2,6-hexylene, the isomers of heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene,
  • R 3 as cycloalkylene preferably contains from 4 to 6 and especially 5 or 6 carbon atoms. Some examples are cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene.
  • R 3 as cycloalkylene is preferably 1,2- or 1,3-cyclopentylene and 1,2-, 1,3- and 1,4-cyclohexylene.
  • R 3 as arylene is preferably C 6 -C 14 arylene.
  • Examples are 1,2-, 1,3- and 1,4-phenylene, 2,3-, 2,7- or 2,8-naphthylene, and biphenylenes of the formula ##STR1## wherein X is a direct bond, --CH 2 --, CH 3 CH ⁇ ,(CH 3 ) 2 C ⁇ , cyclohexylidene, --O--, --S--, --CO--, --CO 2 --, --SO--, --SO 2 --, --NH--, --CO--NH--, --N(C 1 -C 4 alkyl)-- or --CO--N(C 1 -C 4 alkyl)-.
  • R 3 is linear or branched alkylene having from 2 to 20 carbon atoms, especially from 4 to 14 carbon atoms.
  • Cyclic oligomeric carbohydrates from which the radical A is derived are known. They can contain, for example, from 6 to 8 identical or different monosaccharide units. Examples of monosaccharides are mentioned below. Some preferred examples are ⁇ -, ⁇ -and ⁇ -cyclodextrin. Derivatives that come into consideration are derivatives substituted in the 6-position by a monosaccharide, oligosaccharide, C 1 -C 12 alkyl, C 2 -C 4 hydroxyalkyl or by C 1 -C 12 acyl, for example 6-methyl-, 6-hydroxyethyl-, 6-hydroxypropyl-, 6-acetyl- and 6-maltosyl-cyclodextrin.
  • monomeric and linear or branched oligomeric carbohydrates are to be understood as being saccharides, for example mono- and oligosaccharides, such as mono-, di-, tri-, tetra- and penta-saccharides up to deca-saccharides.
  • the oligosaccharides preferably contain from 2 to 8 and especially from 2 to 6 identical or different saccharide units.
  • the mono- and oligo-saccharides are aldoses or ketoses.
  • the monosaccharide is an aldopentose, aldohexose, ketopentose or ketohexose.
  • Examples of an aldopentose are D-ribose, D-arabinose, D-xylose and D-lyxose; examples of an aldohexose are D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose and D-talose, examples of a ketopentose are D-ribulose and D-xylulose, and examples of a ketohexose are D-psicose, D-fructose, D-sorbose and D-tagatose.
  • Examples of a disaccharide are trehalose, maltose, isomaltose, cellobiose, gentiobiose, saccharose and lactose.
  • a trisaccharide is, for example, raffinose or panose.
  • oligomers that come into consideration are, for example, oligomeric decomposition products of polysaccharides, for example, of starch, dextran, cellulose, curdlan, pullulan and chitin. Somes examples are dextrins, maltotetraose, maltohexaose and chitoheptaose.
  • Derivatives of the monomeric and linear or branched oligomeric carbohydrates that may be mentioned are, for example, those substituted in the 1- and/or 2-and/or 3-position(s) by C 1 -C 12 alkyl, C 2 -C 4 hydroxyalkyl and C 1 -C 12 acyl.
  • Other suitable derivatives are, for example, natural and synthetic nucleosides and also oligonucleotides comprising from 2 to 20, preferably from 2 to 10, such nucleosides which may be identical or different.
  • the group R is allyl, propargyl, p-vinylphenyl, p-vinylbenzyl or a radical of the formula R 1 CH ⁇ CR 2 --wherein R 1 is H or C 1 -C 6 alkyl and R 2 is H, C 1 -C 6 alkyl or phenyl.
  • R 1 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms.
  • the alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl and n-butyl.
  • R 1 as alkyl is especially methyl or ethyl.
  • R 1 is H, methyl or ethyl. R 1 is especially H.
  • R 2 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms.
  • the alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • R 2 is preferably H, methyl, ethyl, propyl or butyl.
  • R 1 is H and R 2 is H, methyl, ethyl, n-propyl or n-butyl.
  • R 1 and R 2 are especially each H.
  • the invention relates also to a process for the preparation of the compounds of formulae I and Ia, wherein a divinyldicarboxylic acid ester of formula II
  • R 1 and R 2 are as defined below and R 3 and Y are as defined above, is
  • the compounds of formula II are known or can be prepared in accordance with known processes, for example in accordance with the procedures described by D. Swern et al., in Organic Synthesis Coll. Vol. IV, Wiley, N.Y., pp 977-980 (1963) or by E. S. Rothman et al., in J. Org. Chem. 27, pp 3123-3127 (1962).
  • the carbohydrates of the formulae A--OH and A 1 --CH 2 OH are likewise known and commercially available.
  • the transesterification reactions in reaction step (a) are advantageously carried out in a buffer at temperatures of from 0° to 150° C.
  • Inert, polar and water-miscible solvents are advantageously added to the reaction mixture. Suitable solvents are especially alkanols, for example methanol, ethanol, propanol and butanol, or acetone, tetrahydrofuran, dioxane and dimethylformamide.
  • the isolation of the reaction products is effected in a manner known per se, for example by precipitation, filtration and subsequent drying. The products can be purified by elutriation, reprecipitation or by chromatographic methods.
  • the transesterification reactions in reaction step (b) are advantageously carried out in an inert and polar solvent at temperatures of from 0° to 150° C.
  • Suitable solvents are especially diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, hexane, cyclohexane, methylcyclohexane, benzene, toluene and xylene.
  • the isolation and purification of the products can be carried out as above.
  • Transesterification and amidation reactions in accordance with process step (c) are known to the person skilled in the art.
  • An example of a lipolytic enzyme that may be mentioned is the lipase of Humicola lanuginosa.
  • the reactions are advantageously carried out under an inert gas, for example a noble gas or nitrogen.
  • the compounds of formulae I and Ia are uniform monoacylated monomers having a radically polymerisable group in the ester group which can be polymerised in known manner, for example with the addition of radical initiators, to form linear homopolymers or linear or cross-linked copolymers in which the hydrophilic carbohydrate group is bonded to the polymer backbone by way of a flexible side chain and in which the properties of that group are largely retained.
  • the invention relates also to polymers that, based on the polymer, comprise
  • the polymers according to the invention can have an average molecular weight (weight average) of from 500 to 2,000,000, preferably from 1000 to 1,000,000 and especially from 1000 to 500,000.
  • the linear polymers according to the invention can have, for example, molecular weights of from 500 to 200,000, preferably from 500 to 100,000 and especially from 500 to 50,000.
  • R a preferably contains from 2 to 12, especially from 2 to 10 and more especially from 2 to 8 carbon atoms.
  • the radical R a may be a trivalent ethanetriyl, phenylene-ethylene, phenylenemethyl-ethylene or ethenetriyl group.
  • the ethanetriyl groups can be unsubstituted or substituted by alkyl, the ethanetriyl groups so substituted preferably containing from 2 to 12, especially from 2 to 10 and more especially from 2 to 8 carbon atoms.
  • Some examples are ethanetriyl, propane-1,2,3-triyl, butane-1,2,4-triyl, pentane-1,2,5-triyl, hexane-1,2,6-triyl, heptane-1,2,7-triyl, octane-1,2,8-triyl, --CH 2 --CH(C 6 H 4 --)-- and --CH 2 --CH(C 6 H 4 CH 2 --)--.
  • the ethenetriyl group can be, for example, a group of the formula --HC ⁇ C(C m H 2m --)-- or --(C 1 -C 9 alkyl)C ⁇ C(C m H 2m --)-- wherein m is an integer from 1 to 10, preferably from 1 to 6 and especially from 1 to 4, and the total number of carbon atoms is from 3 to 12, preferably from 3 to 8 and especially from 3 to 6.
  • An example is --HC ⁇ C(CH 2 --)--.
  • Component i) can be present, for example, in an amount of from 0.5 to 100 mol %, preferably from 1 to 100 mol %, especially from 5 to 100 mol %, more especially from 10 to 100 mol % and most especially from 20 to 100 mol %.
  • the content of the comonomer units ii) and iii) depends essentially on the desired properties.
  • Component ii) can be present, for example, in an amount of from 99.5 to 0.5 mol %, preferably from 99 to 1 mol %, especially from 95 to 1 mol %, more especially from 90 to 1 mol % and most especially from 80 to 1 mol %.
  • Component iii) can be present, for example, in an amount of from 70 to 0.01 mol %, preferably from 60 to 0.05 %, especially from 50 to 0.1 mol %, more especially from 40 to 0.5 mol % and most especially from 30 to 1 mol %.
  • the group R a is a radical of the formula --CH 2 --CH(CH 2 --)--, --CH 2 --CH(C 6 H 4 --)--, --CH 2 --CH(C 6 H 4 CH 2 --)--, --HC ⁇ C(CH 2 --)-- or --(R 1 )CH--C(R 2 ) ⁇ wherein R 1 is H or C 1 -C 6 alkyl and R 2 is H, C 1 -C 6 alkyl or phenyl.
  • component i) correspond to formula IV or IVa ##STR3## wherein R 1 is H or C 1 -C 6 alkyl and R 2 is H, C 1 -C 6 alkyl or phenyl, and A, A 1 , R 3 and Y are as defined above, including preferred forms.
  • R 1 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms.
  • the alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl and n-butyl.
  • R 1 as alkyl is especially methyl or ethyl.
  • R 1 is H, methyl or ethyl. R 1 is especially H.
  • R 2 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms.
  • the alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.
  • R 2 is preferably H, methyl, ethyl, propyl or butyl.
  • R 1 is H and R 2 is H, methyl, ethyl, n-propyl or n-butyl. R 1 and R 2 are more especially each H.
  • olefin monomers from which the structural elements of component ii) can be derived are known.
  • the olefin monomers are preferably ethylene which is unsubstituted or substituted by halogen, --OH, --CN, pyrrolidonyl, C 1 -C 12 alkyl, phenyl, C 1 -C 4 alkylphenyl, C 1 -C 4 alkoxyphenyl, halophenyl, hydroxyphenyl, C 1 -C 4 alkylhydroxyphenyl, C 1 -C 4 alkoxyhydroxyphenyl, chloro- or bromo-hydroxyphenyl, C 1 -C 4 alkoxy, phenoxy, C 1 -C 4 alkylphenoxy, benzyl, benzyloxy, --COO.sup. ⁇ M.sup. ⁇ , --COOR 4 , --COOCH 2 CH(OH)CH 2 OH, --COBR 5 --OH, --COO--(R 6 R 7
  • R 5 is linear or branched C 2 -C 18 alkylene, poly(C 2 -C 6 oxaalkylene) having from 2 to 6 oxaalkylene units, C 5 -C 8 cycloalkylene, phenylene, benzylene or xylylene
  • B is --O--, --N(C 1 -C 6 alkyl)-- or --NH--
  • R 6 , R 7 and R 8 are each independently of the oth C 1 -C 6 alkyl or C 1 -C 6 alkoxy and n is a number from 1 to 30.
  • R 4 can be linear or branched C 1 -C 18 alkyl, preferably C 1 -C 12 alkyl and especially C 1 -C 6 -alkyl.
  • R 4 as cycloalkyl is especially cyclopentyl or cyclohexyl.
  • R 4 is (C 1 -C 12 alkyl)cycloalkyl
  • the cycloalkyl is especially cyclopentyl or cyclohexyl and the alkyl group can be linear or branched and preferably contains from 1 to 6, especially from 1 to 4, carbon atoms.
  • R 4 is alkylphenyl or alkylbenzyl
  • the alkyl group can be linear or branched and preferably contains from 1 to 6, especially from 1 to 4, carbon atoms.
  • R 5 as alkylene preferably contains from 2 to 12, especially from 2 to 8 and more especially from 2 to 6, carbon atoms.
  • Examples are ethylene and the isomers of propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tetradecylene, hexadecylene and octadecylene.
  • Ethylene, 1,2-and 1,3-propylene, 1,2-, 1,3- and 1,4-butylene, 1,2-, 1,3-, 1,4- and 1,5-pentylene and 1,2-, 1,3-, 1,4-, 1,5- and 1,6-hexylene are preferred.
  • R 5 as poly(oxaalkylene) preferably contains from 2 to 4 oxaalkylene units and preferably from 2 to 4, especially 2 or 3, carbon atoms in the alkylene radical.
  • R 5 as cycloalkylene is especially cyclopentylene or cyclohexylene.
  • R 6 , R 7 and R 8 are preferably C 1 -C 4 alkyl or C 1 -C 4 alkoxy and are especially methyl, ethyl, methoxy or ethoxy.
  • the index n is preferably a number from 1 to 20, especially from 1 to 10.
  • M.sup. ⁇ as an ammonium cation can be, for example, NH 4 .sup. ⁇ or the cation of a primary amine having from 1 to 12 carbon atoms, of a secondary amine having from 2 to 18 carbon atoms or of a tertiary amine having from 3 to 24 carbon atoms, or is quaternary ammonium having from 4 to 30, preferably from 4 to 20, carbon atoms.
  • component ii) comprises structural units of formula IV ##STR4## wherein R 11 is H, C 1 -C 6 alkyl, --COOR 4 or --COO.sup. ⁇ M.sup. ⁇ ,
  • R 9 is H, F, Cl, CN or C 1 -C 6 alkyl
  • R 10 is H, --F, --Cl, --CN, pyrrolidonyl, R 12 O--, C 1 -C 12 alkyl, --OH, --COO.sup. ⁇ M.sup. ⁇ , --COOR 4 , --COOCH 2 CH(OH)CH 2 OH, --CONH 2 , --CONH(C 1 -C 4 alkyl), --CON(C 1 -C 4 alkyl) 2 , --COBR 5 --OH, --OCO--R 4 , --COO--(R 6 R 7 SiO) n --SiR 6 R 7 R 8 , --COBR 5 --O--(R 6 R 7 SiO) n --SiR 6 R 7 R 8 , phenyl, or phenyl substituted by --OH and/or by one or two methyl, methoxy, Cl or Br,
  • M.sup. ⁇ is H.sup. ⁇ , an alkali metal cation or an ammonium cation
  • R 4 is C 1 -C 18 alkyl, C 5 -C 7 cycloalkyl, (C 1 -C 12 alkyl)-C 5 -C 7 cycloalkyl, phenyl, (C 1 -C 12 alkyl)phenyl, benzyl or (C 1 -C 12 alkyl)benzyl,
  • R 12 is linear or branched C 2 -C 18 alkylene, poly(C 2 -C 6 oxaalkylene) having from 2 to 6 oxaalkylene units, C 5 -C 8 cycloalkylene, phenylene, benzylene or xylylene,
  • B is --O--, --N(C 1 -C 4 alkyl)- or --NH--,
  • R 6 , R 7 and R 8 are methyl, ethyl, methoxy or ethoxy
  • n is 0 or a number from 1 to 20, preferably from 1 to 12.
  • R 11 is preferably H. When R 11 is alkyl it is preferably methyl or ethyl. When R 11 is --COOR 4 , R 4 is preferably C 1 -C 12 alkyl, especially C 1 -C 6 alkyl.
  • R 9 is alkyl it is preferably C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl and n-butyl.
  • R 9 is preferably H, Cl or C 1 -C 4 alkyl.
  • R 12 is preferably C 1 -C 12 alkyl, especially C 1 -C 6 alkyl.
  • R 10 is alkyl it preferably contains from 1 to 6, especially from 1 to 4, carbon atoms.
  • R 4 is preferably C 1 -C 12 alkyl, especially C 1 -C 6 alkyl, cyclopentyl or cyclohexyl.
  • R 4 is preferably C 1 -C 12 alkyl, especially C 1 -C 6 alkyl, phenyl or benzyl.
  • R 10 is the group --COOR 5 OH
  • the preferences mentioned above for R 5 apply.
  • R 10 is a group --CONH(C 1 -C 4 alkyl) or --CON(C 1 -C 4 alkyl) 2 , it is preferably --CONHCH 3 , --CONHC 2 H 5 , CON(CH 3 ) 2 or --CON(C 2 H 5 ) 2 .
  • R 11 is H
  • R 9 is H
  • R 10 is pyrrolidonyl, --F, --Cl, --CN, --OH, C 1 -C 4 alkyl, C 1 -C 6 alkoxy, --COO--C 1 -C 6 alkyl, --COO--R 5 --OH, --COOM.sup. ⁇ , --OOC--C 1 -C 6 alkyl, --COOCH 2 CH(OH)CH 2 OH, --CONH 2 , --CONH(C 1 -C 4 alkyl), --CON(C 1 -C 4 alkyl) 2 , --COO--(R 6 R 7 SiO) n --SiR 6 R 7 R 8 , --COBR 5 --O--(R 6 R 7 SiO) n --SiR 6 R 7 R 8 , phenyl, methylphenyl, dimethylphenyl, chlorophenyl, dich
  • R 11 is H
  • R 9 is H or methyl
  • R 10 is pyrrolidonyl, --CN, --COOH, --COO--C y H 2y --OH wherein y is from 2 to 6, especially 2 or 3, --CON(CH 3 ) 2 , --COO--CH 2 CH(OH)CH 2 OH and --COO--CH 2 CH 2 --O--[Si(OCH 3 ) 2 --O] n --Si(OCH 3 ) 3 or --COO--CH 2 CH 2 --O--[Si(OC 2 H 5 ) 2 --O] n --Si(OC 2 H 5 ) 3 wherein n is from 1 to 8 and preferably from 2 to 6.
  • copolymers according to the invention can be block polymers, or copolymer having an alternating or statistical distribution of the structural units.
  • Component iii) can comprise, for example, structural units of butadiene, isoprene and chloroprene.
  • Other suitable structural units can be derived from diacrylates or dimethacrylates of diols or from diacrylamides or dimethacrylamides of diamines.
  • the alcohols and diamines may be those of the formula HY--C x H 2x --YH wherein x is a number from 2 to 12, preferably from 2 to 6, and Y is --O--, --NH-- or --N(C 1 -C 4 alkyl)-.
  • Suitable diols are also polyoxaalkylenediols of the formula HO--(C n H 2n O) y --H wherein n is a number from 2 to 6, preferably from 2 to 4 and especially 2 or 3, and y is a number from 2 to 20, preferably from 2 to 10, especially from 2 to 6 and more especially from 2 to 4.
  • Some examples are ethylene glycol, 1,2- and 1,3-propylene glycol, 1,2-, 1,3- and 1,4-propylene glycol and the isomers of pentylene glycol, hexylene glycol, heptylene glycol, octylene glycol, nonylene glycol, decylene glycol, undecylene glycol and dodecylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, di-1,2-propylene glycol, tri-1,2-propylene glycol, oligomeric polyoxaalkylene glycols having from 4 to 12 identical or different oxaethylene or oxapropylene radicals.
  • the polymers according to the invention may comprise as a fourth component iiii) up to 10 mol %, preferably from 0.01 to 5 mol %, of radicals of trifunctional ethylenically unsaturated compounds, the molar percentages in the polymer totalling 100 mol %.
  • radicals of trifunctional ethylenically unsaturated compounds the molar percentages in the polymer totalling 100 mol %. Examples that may be mentioned are the acrylate and methacrylate triesters of trimethylolpropane or methyltrimethylolpropane.
  • the preparation of the polymers according to the invention can be carried out in accordance with customary methods by radical polymerisation, including photochemical-radical polymerisation, suitable methods being, for example, block, emulsion, solution or interfacial polymerisation. Isolation and purification can also be carried out in accordance with the methods customary in polymer chemistry. Other details are described in the Examples.
  • the polymers according to the invention are colourless transparent to white and opaque solids having a very high degree of hydrophilicity. Depending upon the composition, they are water-soluble or are soluble or swellable in water or other dipolar and aprotic or protic solvents, and are able to form gels or hydrogels or non-swellable polymers with strongly hydrophilic surfaces.
  • the polymers may, according to their composition, be hydrophilic, amphiphilic or hydrophobic.
  • the properties of the polymers can be adjusted specifically by the choice and amounts of monomers and of the spacer in the monomers according to the invention. The monomers and polymers are easily obtainable. Some of the polymers are physiologically acceptable and are distinguished by their constant good biological and physicochemical properties. Some of the polymers according to the invention are also biodegradable. These polymers have a wide variety of possible uses in technology.
  • the polymers according to the invention have film-forming properties. When aqueous or organic solutions are concentrated by evaporation there are formed transparent, solid and possibly water-containing films which are air- and moisture-permeable. On the basis of that property and their water-storing action they are suitable also as moisturisers for the skin or the mucosa in cosmetic preparations and pharmaceutical compositions, as agents for maintaining joint mobility and for wound dressings. Cosmetic preparations are, for example, skin-care and hair-care preparations and deodorants.
  • the polymers according to the invention, and especially gels prepared therefrom, are also suitable for the manufacture of compositions having controlled release of active ingredient over a prolonged period, for example pharmaceutical and pesticidal active ingredients or aromatic substances.
  • the water-soluble polymers according to the invention also have a viscosity-increasing and dispersing action and can be used as surfactants and thickeners. They are suitable, for example, as additives in suspensions, emulsions, dispersions and aqueous solutions, for example in the preparation of foodstuffs or biologically active ingredient concentrates and colouring and pigmenting preparations.
  • the polymers according to the invention can be used in a manner known per se to prepare films and foils that can be used as membranes or as wound dressings; alternatively, capsules for active ingredients or coated active ingredients can be prepared in a manner known per se, the active ingredient being released into the environment in a delayed and continuous manner.
  • solid carrier materials for example metals, semimetals, ceramics, glass, metal and semimetal oxides or nitrides, wood, paper and plastics
  • solid carrier materials for example metals, semimetals, ceramics, glass, metal and semimetal oxides or nitrides, wood, paper and plastics
  • the polymers according to the invention can be used, for example, also in the manufacture of soft contact lenses from corresponding hydrogels or for the manufacture of hard contact lenses having permanently hydrophilic surfaces or for the modification of the surfaces of contact lenses or for the cleaning of contact lenses.
  • the invention relates also to the use of the water-soluble polymers according to the invention as thickeners and surfactants.
  • the invention relates also to the use of the polymers according to the invention as a carrier for active ingredients to provide controlled release of the active ingredient.
  • the invention relates also to the use of the polymers according to the invention for the manufacture, modification or cleaning of contact lenses.
  • esters are prepared in accordance with the procedure of Swern, D., Jordan, E. F., in Organic Syntheses Coll. Vol. IV, Wiley, New York, 1963, pp 977-980.
  • ⁇ , ⁇ -Dicarboxylic acid diisopropenyl esters are prepared in accordance with the procedure of Rothman, E. S., Serota, S., Perlstein, T., Swern, D., J. Org. Chem. 27 (1962), 3123-3127.
  • a transparent, water-resistant and hydrophilic film (contact angle about 45°) is obtained when the latex described according to Example C1 is spread onto a glass surface and dried for 3 days under a current of hot air at 100° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Physics & Mathematics (AREA)
  • Polymers & Plastics (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Saccharide Compounds (AREA)
  • Eyeglasses (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Macromonomer-Based Addition Polymer (AREA)
  • Materials For Medical Uses (AREA)

Abstract

Compounds of formulae I and Ia
R--Y--CO--R.sub.3 --CO--O--A                               (I),
R--Y--CO--R.sub.3 --CO--O--CH.sub.2 --A.sub.1              (Ia),
wherein
R is a radically polymerisable hydrocarbon group,
R3 is a direct bond, linear or branched C1 -C22 alkylene, C3 -C8 cycloalkylene or C6 -C14 arylene,
A is the radical, reduced by a hydroxy group in a 2- or 3position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
A1 is the radical, reduced by a hydroxymethyl group, of a monomeric or linear oligomeric carbohydrate or of a derivative of such a carbohydrate, and
Y is --O--, --NH-- or --N(C1 -C6 alkyl)-.
Homo- and co-polymers having those monomers have, depending upon their composition, hydrophilic, amphiphilic or hydrophobic properties and are able to form hydrogels. The polymers can be used, for example, as surfactants, thickeners, carriers for biologically active ingredients or in the manufacture of contact lenses.

Description

This application is a continuation of International Application Ser. No. PCT/EP93/03236, filed Nov. 19, 1993.
The invention relates to polymerisable esters of carbohydrates and dicarboxylic acids having an ester group containing radically polymerisable radicals, to homopolymers and copolymers therefrom, to processes for their preparation and to their use.
The introduction of polymerisable groups into carbohydrates such as, for example, cyclodextrins is desirable owing to their properties, especially their high degree of hydrophilicity, their specific complex-forming behaviour and their bioactivity. Acrylate-containing, methacrylate-containing and cinnamoyl-containing cyclodextrins and polymers therefrom have been described, for example, by A. P. Croft et al. in Tetrahedron, Vol. 39, No. 9, pages 1425 to 1427 (1983). The polymerisable groups are regiospecifically bonded in the 2- or 3-positions. They are obtained by the reaction of suitable activated esters, namely nitrophenylcarboxylic acid esters, with a cyclodextrin. It is generally very difficult completely to remove the resulting nitrophenol, since cyclodextrins form inclusion compounds with those organic compounds. Owing to the fact that nitrophenols are not physiologically acceptable, have a polymerisation-inhibiting action and are also very expensive to purify, polymers from such polymerisable cyclodextrins can be used only to a limited extent.
It is also known to prepare homopolymers or copolymers from acrylate or methacrylate esters of sugars. The acylation of sugars is less regioselective, however, and always results in non-uniform compound mixtures which also comprise compounds having more than one polymerisable acyl group. Polymers from those mixtures therefore always comprise undesired and cross-linked or branched products having a tendency to precipitate out of solutions. In addition, the natural properties of the sugar radicals that are desirable for many applications are lost as a result of multiple substitution. Furthermore, the ester bond of those acrylates and methacrylates is relatively rigid. The areas of application are considerably limited by those disadvantages. In order to obtain regioselectively substituted polymers of an acrylate ester of galactose, it has been proposed to acryloylate the diacetonide of galactose, followed by polymerisation and subsequent unblocking (CA 70:29704p). That complex process is uneconomical, however.
WO 91/17255 describes the enzyme-catalysed preparation of polymers from sugars and dicarboxylic acid esters by means of a regioselective diacylation, wherein the sugar radicals are bonded as comonomers in the polymer backbone and, as a consequence, bioactive properties are virtually lost.
It has now been found that cyclosaccharides can be monoacylated regioselectively in the 2- or 3-positions or the primary hydroxy group of monomeric, dimeric or linear oligomeric saccharides can be monoacylated regioselectively, by carrying out the acylation with monovinyl or divinyl esters of dicarboxylic acids. Surprisingly, despite the presence of two ester groups of equal reactivity no dimers or polysubstituted products are obtained. Vinyl ester groups can be transesterified with unsaturated alkanols to form other radically polymerisable monomers or can be amidated with unsaturated amines. Those monomers and the monovinyl esters of sugars are especially suitable for the preparation of linear polymers, the saccharide group being bonded to a flexible spacer. As a consequence of the specific monoacylation and the flexible bonding to a polymer backbone, the properties of the saccharide radicals are largely retained also in the polymers.
The invention relates to compounds of formulae I and Ia
R--Y--CO--R.sub.3 --CO--O--A                               (I),
R--Y--CO--R.sub.3 --CO--O--CH.sub.2 --A.sub.1              (Ia),
wherein
R is a radically polymerisable hydrocarbon group,
R3 is a direct bond, linear or branched C1 -C22 alkylene, C3 -C8 cycloalkylene or C6 -C14 arylene,
A is the radical, reduced by a hydroxy group in a 2- or 3-position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
A1 is the radical, reduced by a hydroxymethyl group, of a monomeric or linear or branched oligomeric carbohydrate or of a derivative of such a carbohydrate, and
Y is --O--, --NH-- or --N(C1 -C6 alkyl)-.
R preferably contains from 2 to 12, especially from 2 to 10 and more especially from 2 to 8, carbon atoms. The radical R can contain ethene or ethyne groups as radically polymerisable groups. R may be, for example, alkenyl, alkynyl, vinylphenyl or vinylbenzyl. Some examples of alkenyl are vinyl, allyl, 1-propen-2-yl, 1-buten-2- or -3- or -4-yl, 2-buten-3-yl, the isomers of pentenyl, hexenyl, octenyl, decenyl and dodecenyl. Vinyl, allyl and 1-propen-2-yl are preferred. R as alkynyl is preferably an alkynylalkyl radical, for example HCC--Cm H2m -- or C1 -C9 alkyl-CC--Cm H2m --wherein m is an integer from 1 to 10, preferably from 1 to 6 and especially from 1 to 4, and the total number of carbon atoms is from 3 to 12, preferably from 3 to 8 and especially from 3 to 6. Some examples of alkynyl are propargyl, 1-butyn-3- or -4-yl, 1-pentyn-3- or -4- or -5-yl, 2-pentyn-4- or -5-yl, 1-hexyn-3- or -4- or -5- or -6-yl, 2-hexyn-4- or -5- or -6-yl, and 3-hexyn-5- or -6-yl.
The group Y is preferably --O--, --NH--, --Nmethyl-- or --Nethyl-- and especially --O-- or --NH--.
R3 as alkylene preferably contains from 2 to 20 and especially from 4 to 18 carbon atoms. Some examples are methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene, 1,1-, 2,2- or 3,3-pentylidene or 1,1-, 2,2- or 3,3-hexylidene, 1,2-ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3-, 2,3- or 1,4-butylene, 1,2-, 1,3-, 1,4-, 1,5-, 2,3-, 2,4- or 2,5-pentylene, 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 2,3-, 2,4 -, 2,5- or 2,6-hexylene, the isomers of heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene and eicosylene.
R3 as cycloalkylene preferably contains from 4 to 6 and especially 5 or 6 carbon atoms. Some examples are cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene. R3 as cycloalkylene is preferably 1,2- or 1,3-cyclopentylene and 1,2-, 1,3- and 1,4-cyclohexylene.
R3 as arylene is preferably C6 -C14 arylene. Examples are 1,2-, 1,3- and 1,4-phenylene, 2,3-, 2,7- or 2,8-naphthylene, and biphenylenes of the formula ##STR1## wherein X is a direct bond, --CH2 --, CH3 CH═,(CH3 )2 C═, cyclohexylidene, --O--, --S--, --CO--, --CO2 --, --SO--, --SO2 --, --NH--, --CO--NH--, --N(C1 -C4 alkyl)-- or --CO--N(C1 -C4 alkyl)-.
In a preferred from, R3 is linear or branched alkylene having from 2 to 20 carbon atoms, especially from 4 to 14 carbon atoms.
Cyclic oligomeric carbohydrates from which the radical A is derived are known. They can contain, for example, from 6 to 8 identical or different monosaccharide units. Examples of monosaccharides are mentioned below. Some preferred examples are α-, β-and γ-cyclodextrin. Derivatives that come into consideration are derivatives substituted in the 6-position by a monosaccharide, oligosaccharide, C1 -C12 alkyl, C2 -C4 hydroxyalkyl or by C1 -C12 acyl, for example 6-methyl-, 6-hydroxyethyl-, 6-hydroxypropyl-, 6-acetyl- and 6-maltosyl-cyclodextrin.
Within the scope of this invention, monomeric and linear or branched oligomeric carbohydrates are to be understood as being saccharides, for example mono- and oligosaccharides, such as mono-, di-, tri-, tetra- and penta-saccharides up to deca-saccharides. The oligosaccharides preferably contain from 2 to 8 and especially from 2 to 6 identical or different saccharide units. In a preferred form the mono- and oligo-saccharides are aldoses or ketoses. In an especially preferred form the monosaccharide is an aldopentose, aldohexose, ketopentose or ketohexose.
Examples of an aldopentose are D-ribose, D-arabinose, D-xylose and D-lyxose; examples of an aldohexose are D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose and D-talose, examples of a ketopentose are D-ribulose and D-xylulose, and examples of a ketohexose are D-psicose, D-fructose, D-sorbose and D-tagatose.
Examples of a disaccharide are trehalose, maltose, isomaltose, cellobiose, gentiobiose, saccharose and lactose.
A trisaccharide is, for example, raffinose or panose.
Other oligomers that come into consideration are, for example, oligomeric decomposition products of polysaccharides, for example, of starch, dextran, cellulose, curdlan, pullulan and chitin. Somes examples are dextrins, maltotetraose, maltohexaose and chitoheptaose.
Derivatives of the monomeric and linear or branched oligomeric carbohydrates that may be mentioned are, for example, those substituted in the 1- and/or 2-and/or 3-position(s) by C1 -C12 alkyl, C2 -C4 hydroxyalkyl and C1 -C12 acyl. Other suitable derivatives are, for example, natural and synthetic nucleosides and also oligonucleotides comprising from 2 to 20, preferably from 2 to 10, such nucleosides which may be identical or different.
In a preferred form, the group R is allyl, propargyl, p-vinylphenyl, p-vinylbenzyl or a radical of the formula R1 CH═CR2 --wherein R1 is H or C1 -C6 alkyl and R2 is H, C1 -C6 alkyl or phenyl.
When R1 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl and n-butyl. R1 as alkyl is especially methyl or ethyl.
In a preferred form, R1 is H, methyl or ethyl. R1 is especially H.
When R2 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. R2 is preferably H, methyl, ethyl, propyl or butyl.
In an especially preferred form, R1 is H and R2 is H, methyl, ethyl, n-propyl or n-butyl. R1 and R2 are especially each H.
The invention relates also to a process for the preparation of the compounds of formulae I and Ia, wherein a divinyldicarboxylic acid ester of formula II
R.sub.1 CH═CR.sub.2 --O--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1(II),
or a monovinyl ester of formula IIa
R"--Y--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1        (IIa),
wherein R1 and R2 are as defined below and R3 and Y are as defined above, is
(a) transesterified with a cyclic-oligomeric carbohydrate of the formula A--OH, or with a derivative thereof, wherein A is as defined above, or
(b) transesterified in the presence of lipolytic enzymes with a monomeric or linear oligomeric carbohydrate of the formula A1 --CH2 OH, or with a derivative thereof, wherein A1 is as defined above, and
(c) if desired the resulting compound of formula I or Ia wherein R is a radically polymerisable vinyl ester group is transesterified or amidated with an alcohol of the formula R'--OH, with an amine R'NH2 or with an amine R'NHC1 -C4 alkyl, with R' and R" each independently of the other being a non-vinylic radically polymerisable hydrocarbon group.
The compounds of formula II are known or can be prepared in accordance with known processes, for example in accordance with the procedures described by D. Swern et al., in Organic Synthesis Coll. Vol. IV, Wiley, N.Y., pp 977-980 (1963) or by E. S. Rothman et al., in J. Org. Chem. 27, pp 3123-3127 (1962). The carbohydrates of the formulae A--OH and A1 --CH2 OH are likewise known and commercially available.
The transesterification reactions in reaction step (a) are advantageously carried out in a buffer at temperatures of from 0° to 150° C. Inert, polar and water-miscible solvents are advantageously added to the reaction mixture. Suitable solvents are especially alkanols, for example methanol, ethanol, propanol and butanol, or acetone, tetrahydrofuran, dioxane and dimethylformamide. The isolation of the reaction products is effected in a manner known per se, for example by precipitation, filtration and subsequent drying. The products can be purified by elutriation, reprecipitation or by chromatographic methods. The transesterification reactions in reaction step (b) are advantageously carried out in an inert and polar solvent at temperatures of from 0° to 150° C. Suitable solvents are especially diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, acetone, methyl isobutyl ketone, hexane, cyclohexane, methylcyclohexane, benzene, toluene and xylene. The isolation and purification of the products can be carried out as above. Transesterification and amidation reactions in accordance with process step (c) are known to the person skilled in the art. An example of a lipolytic enzyme that may be mentioned is the lipase of Humicola lanuginosa. The reactions are advantageously carried out under an inert gas, for example a noble gas or nitrogen.
The compounds of formulae I and Ia are uniform monoacylated monomers having a radically polymerisable group in the ester group which can be polymerised in known manner, for example with the addition of radical initiators, to form linear homopolymers or linear or cross-linked copolymers in which the hydrophilic carbohydrate group is bonded to the polymer backbone by way of a flexible side chain and in which the properties of that group are largely retained.
The invention relates also to polymers that, based on the polymer, comprise
i) 0.1 to 100 mol % of at least one structural element of formula III and/or IIIa ##STR2## wherein Ra is the radical of a radically polymerised group and R3, A, A1 and Y are as defined above,
ii) 99.9 to 0 mol % of at least one structural element, different from formulae III and IIIa, of a radically polymerised olefin, and
iii) 80 to 0 mol % of at least one structural element of a radically polymerised diolefin, the molar percentages totalling 100%.
The polymers according to the invention can have an average molecular weight (weight average) of from 500 to 2,000,000, preferably from 1000 to 1,000,000 and especially from 1000 to 500,000. The linear polymers according to the invention can have, for example, molecular weights of from 500 to 200,000, preferably from 500 to 100,000 and especially from 500 to 50,000.
Ra preferably contains from 2 to 12, especially from 2 to 10 and more especially from 2 to 8 carbon atoms. The radical Ra may be a trivalent ethanetriyl, phenylene-ethylene, phenylenemethyl-ethylene or ethenetriyl group. The ethanetriyl groups can be unsubstituted or substituted by alkyl, the ethanetriyl groups so substituted preferably containing from 2 to 12, especially from 2 to 10 and more especially from 2 to 8 carbon atoms. Some examples are ethanetriyl, propane-1,2,3-triyl, butane-1,2,4-triyl, pentane-1,2,5-triyl, hexane-1,2,6-triyl, heptane-1,2,7-triyl, octane-1,2,8-triyl, --CH2 --CH(C6 H4 --)-- and --CH2 --CH(C6 H4 CH2 --)--. The ethenetriyl group can be, for example, a group of the formula --HC═C(Cm H2m --)-- or --(C1 -C9 alkyl)C═C(Cm H2m --)-- wherein m is an integer from 1 to 10, preferably from 1 to 6 and especially from 1 to 4, and the total number of carbon atoms is from 3 to 12, preferably from 3 to 8 and especially from 3 to 6. An example is --HC═C(CH2 --)--.
The arrangements and preferences given above apply to R3, A, A1 and Y.
Component i) can be present, for example, in an amount of from 0.5 to 100 mol %, preferably from 1 to 100 mol %, especially from 5 to 100 mol %, more especially from 10 to 100 mol % and most especially from 20 to 100 mol %. The content of the comonomer units ii) and iii) depends essentially on the desired properties. Component ii) can be present, for example, in an amount of from 99.5 to 0.5 mol %, preferably from 99 to 1 mol %, especially from 95 to 1 mol %, more especially from 90 to 1 mol % and most especially from 80 to 1 mol %. Component iii) can be present, for example, in an amount of from 70 to 0.01 mol %, preferably from 60 to 0.05 %, especially from 50 to 0.1 mol %, more especially from 40 to 0.5 mol % and most especially from 30 to 1 mol %.
In a preferred form, the group Ra is a radical of the formula --CH2 --CH(CH2 --)--, --CH2 --CH(C6 H4 --)--, --CH2 --CH(C6 H4 CH2 --)--, --HC═C(CH2 --)-- or --(R1)CH--C(R2)═ wherein R1 is H or C1 -C6 alkyl and R2 is H, C1 -C6 alkyl or phenyl.
In an especially preferred form, the structural elements of component i) correspond to formula IV or IVa ##STR3## wherein R1 is H or C1 -C6 alkyl and R2 is H, C1 -C6 alkyl or phenyl, and A, A1, R3 and Y are as defined above, including preferred forms.
When R1 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl and n-butyl. R1 as alkyl is especially methyl or ethyl.
In a preferred form, R1 is H, methyl or ethyl. R1 is especially H.
When R2 is alkyl it preferably contains from 1 to 4 and especially 1 or 2 carbon atoms. The alkyl is preferably linear. Some examples are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. R2 is preferably H, methyl, ethyl, propyl or butyl.
In an especially preferred form, R1 is H and R2 is H, methyl, ethyl, n-propyl or n-butyl. R1 and R2 are more especially each H.
Numerous olefin monomers from which the structural elements of component ii) can be derived are known. The olefin monomers are preferably ethylene which is unsubstituted or substituted by halogen, --OH, --CN, pyrrolidonyl, C1 -C12 alkyl, phenyl, C1 -C4 alkylphenyl, C1 -C4 alkoxyphenyl, halophenyl, hydroxyphenyl, C1 -C4 alkylhydroxyphenyl, C1 -C4 alkoxyhydroxyphenyl, chloro- or bromo-hydroxyphenyl, C1 -C4 alkoxy, phenoxy, C1 -C4 alkylphenoxy, benzyl, benzyloxy, --COO.sup.⊖ M.sup.⊕, --COOR4, --COOCH2 CH(OH)CH2 OH, --COBR5 --OH, --COO--(R6 R7 SiO)n --SiR6 R7 R8, --COBR5 --O--(R6 R7 SiO)n --SiR6 R7 R8, --CONH2, --CONH(C1 -C6 alkyl), --CON(C1 -C6 alkyl)2 or by --OCO--R4 wherein M.sup.⊕ is H.sup.⊕, an alkali metal cation or an ammonium cation, R4 is C1 -C18 alkyl, C.sub. 5 -C7 cycloalkyl, (C1 -C12 alkyl)-C5 -C7 cycloalkyl, phenyl, (C1 -C12 alkyl)phenyl, benzyl or (C1 -C12 alkyl)benzyl, R5 is linear or branched C2 -C18 alkylene, poly(C2 -C6 oxaalkylene) having from 2 to 6 oxaalkylene units, C5 -C8 cycloalkylene, phenylene, benzylene or xylylene, B is --O--, --N(C1 -C6 alkyl)-- or --NH--, R6, R7 and R8 are each independently of the oth C1 -C6 alkyl or C1 -C6 alkoxy and n is a number from 1 to 30.
R4 can be linear or branched C1 -C18 alkyl, preferably C1 -C12 alkyl and especially C1 -C6 -alkyl. R4 as cycloalkyl is especially cyclopentyl or cyclohexyl. When R4 is (C1 -C12 alkyl)cycloalkyl, the cycloalkyl is especially cyclopentyl or cyclohexyl and the alkyl group can be linear or branched and preferably contains from 1 to 6, especially from 1 to 4, carbon atoms. When R4 is alkylphenyl or alkylbenzyl, the alkyl group can be linear or branched and preferably contains from 1 to 6, especially from 1 to 4, carbon atoms.
R5 as alkylene preferably contains from 2 to 12, especially from 2 to 8 and more especially from 2 to 6, carbon atoms. Examples are ethylene and the isomers of propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tetradecylene, hexadecylene and octadecylene. Ethylene, 1,2-and 1,3-propylene, 1,2-, 1,3- and 1,4-butylene, 1,2-, 1,3-, 1,4- and 1,5-pentylene and 1,2-, 1,3-, 1,4-, 1,5- and 1,6-hexylene are preferred.
R5 as poly(oxaalkylene) preferably contains from 2 to 4 oxaalkylene units and preferably from 2 to 4, especially 2 or 3, carbon atoms in the alkylene radical.
R5 as cycloalkylene is especially cyclopentylene or cyclohexylene.
R6, R7 and R8 are preferably C1 -C4 alkyl or C1 -C4 alkoxy and are especially methyl, ethyl, methoxy or ethoxy. The index n is preferably a number from 1 to 20, especially from 1 to 10.
M.sup.⊕ as an ammonium cation can be, for example, NH4.sup.⊕ or the cation of a primary amine having from 1 to 12 carbon atoms, of a secondary amine having from 2 to 18 carbon atoms or of a tertiary amine having from 3 to 24 carbon atoms, or is quaternary ammonium having from 4 to 30, preferably from 4 to 20, carbon atoms.
In a preferred form, component ii) comprises structural units of formula IV ##STR4## wherein R11 is H, C1 -C6 alkyl, --COOR4 or --COO.sup.⊖ M.sup.⊕,
R9 is H, F, Cl, CN or C1 -C6 alkyl,
R10 is H, --F, --Cl, --CN, pyrrolidonyl, R12 O--, C1 -C12 alkyl, --OH, --COO.sup.⊖ M.sup.⊕, --COOR4, --COOCH2 CH(OH)CH2 OH, --CONH2, --CONH(C1 -C4 alkyl), --CON(C1 -C4 alkyl)2, --COBR5 --OH, --OCO--R4, --COO--(R6 R7 SiO)n --SiR6 R7 R8, --COBR5 --O--(R6 R7 SiO)n --SiR6 R7 R8, phenyl, or phenyl substituted by --OH and/or by one or two methyl, methoxy, Cl or Br,
M.sup.⊕ is H.sup.⊕, an alkali metal cation or an ammonium cation,
R4 is C1 -C18 alkyl, C5 -C7 cycloalkyl, (C1 -C12 alkyl)-C5 -C7 cycloalkyl, phenyl, (C1 -C12 alkyl)phenyl, benzyl or (C1 -C12 alkyl)benzyl,
R12 is linear or branched C2 -C18 alkylene, poly(C2 -C6 oxaalkylene) having from 2 to 6 oxaalkylene units, C5 -C8 cycloalkylene, phenylene, benzylene or xylylene,
B is --O--, --N(C1 -C4 alkyl)- or --NH--,
R6, R7 and R8 are methyl, ethyl, methoxy or ethoxy, and
n is 0 or a number from 1 to 20, preferably from 1 to 12.
R11 is preferably H. When R11 is alkyl it is preferably methyl or ethyl. When R11 is --COOR4, R4 is preferably C1 -C12 alkyl, especially C1 -C6 alkyl.
When R9 is alkyl it is preferably C1 -C4 alkyl, for example methyl, ethyl, n-propyl and n-butyl. R9 is preferably H, Cl or C1 -C4 alkyl.
When R10 is the group R12 --O--, R12 is preferably C1 -C12 alkyl, especially C1 -C6 alkyl. When R10 is alkyl it preferably contains from 1 to 6, especially from 1 to 4, carbon atoms. When R10 is the group --COOR4, R4 is preferably C1 -C12 alkyl, especially C1 -C6 alkyl, cyclopentyl or cyclohexyl. When R10 is the group --OCO--R4, R4 is preferably C1 -C12 alkyl, especially C1 -C6 alkyl, phenyl or benzyl.
When R10 is the group --COOR5 OH, the preferences mentioned above for R5 apply.
When R10 is a group --CONH(C1 -C4 alkyl) or --CON(C1 -C4 alkyl)2, it is preferably --CONHCH3, --CONHC2 H5, CON(CH3)2 or --CON(C2 H5)2.
In a preferred form, R11 is H, R9 is H, --F, --Cl, methyl or ethyl, and R10 is pyrrolidonyl, --F, --Cl, --CN, --OH, C1 -C4 alkyl, C1 -C6 alkoxy, --COO--C1 -C6 alkyl, --COO--R5 --OH, --COOM.sup.⊕, --OOC--C1 -C6 alkyl, --COOCH2 CH(OH)CH2 OH, --CONH2, --CONH(C1 -C4 alkyl), --CON(C1 -C4 alkyl)2, --COO--(R6 R7 SiO)n --SiR6 R7 R8, --COBR5 --O--(R6 R7 SiO)n --SiR6 R7 R8, phenyl, methylphenyl, dimethylphenyl, chlorophenyl, dichlorophenyl, dibromophenyl, methoxyphenyl, dimethoxyphenyl or hydroxyphenyl wherein M.sup.⊕ is trialkylammonium having from 1 to 4 carbon atoms in the alkyl groups and R5 is C2 -C6 alkylene, and R6, R7 and R8 are methyl, ethyl, methoxy or ethoxy, and n is 0 or a number from 1 to 12.
In a very especially preferred form, in formula V R11 is H, R9 is H or methyl, and R10 is pyrrolidonyl, --CN, --COOH, --COO--Cy H2y --OH wherein y is from 2 to 6, especially 2 or 3, --CON(CH3)2, --COO--CH2 CH(OH)CH2 OH and --COO--CH2 CH2 --O--[Si(OCH3)2 --O]n --Si(OCH3)3 or --COO--CH2 CH2 --O--[Si(OC2 H5)2 --O]n --Si(OC2 H5)3 wherein n is from 1 to 8 and preferably from 2 to 6.
The copolymers according to the invention can be block polymers, or copolymer having an alternating or statistical distribution of the structural units.
Component iii) can comprise, for example, structural units of butadiene, isoprene and chloroprene. Other suitable structural units can be derived from diacrylates or dimethacrylates of diols or from diacrylamides or dimethacrylamides of diamines. The alcohols and diamines may be those of the formula HY--Cx H2x --YH wherein x is a number from 2 to 12, preferably from 2 to 6, and Y is --O--, --NH-- or --N(C1 -C4 alkyl)-. Suitable diols are also polyoxaalkylenediols of the formula HO--(Cn H2n O)y --H wherein n is a number from 2 to 6, preferably from 2 to 4 and especially 2 or 3, and y is a number from 2 to 20, preferably from 2 to 10, especially from 2 to 6 and more especially from 2 to 4. Some examples are ethylene glycol, 1,2- and 1,3-propylene glycol, 1,2-, 1,3- and 1,4-propylene glycol and the isomers of pentylene glycol, hexylene glycol, heptylene glycol, octylene glycol, nonylene glycol, decylene glycol, undecylene glycol and dodecylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, di-1,2-propylene glycol, tri-1,2-propylene glycol, oligomeric polyoxaalkylene glycols having from 4 to 12 identical or different oxaethylene or oxapropylene radicals.
The polymers according to the invention may comprise as a fourth component iiii) up to 10 mol %, preferably from 0.01 to 5 mol %, of radicals of trifunctional ethylenically unsaturated compounds, the molar percentages in the polymer totalling 100 mol %. Examples that may be mentioned are the acrylate and methacrylate triesters of trimethylolpropane or methyltrimethylolpropane.
The preparation of the polymers according to the invention can be carried out in accordance with customary methods by radical polymerisation, including photochemical-radical polymerisation, suitable methods being, for example, block, emulsion, solution or interfacial polymerisation. Isolation and purification can also be carried out in accordance with the methods customary in polymer chemistry. Other details are described in the Examples.
The polymers according to the invention are colourless transparent to white and opaque solids having a very high degree of hydrophilicity. Depending upon the composition, they are water-soluble or are soluble or swellable in water or other dipolar and aprotic or protic solvents, and are able to form gels or hydrogels or non-swellable polymers with strongly hydrophilic surfaces. The polymers may, according to their composition, be hydrophilic, amphiphilic or hydrophobic. The properties of the polymers can be adjusted specifically by the choice and amounts of monomers and of the spacer in the monomers according to the invention. The monomers and polymers are easily obtainable. Some of the polymers are physiologically acceptable and are distinguished by their constant good biological and physicochemical properties. Some of the polymers according to the invention are also biodegradable. These polymers have a wide variety of possible uses in technology.
The polymers according to the invention have film-forming properties. When aqueous or organic solutions are concentrated by evaporation there are formed transparent, solid and possibly water-containing films which are air- and moisture-permeable. On the basis of that property and their water-storing action they are suitable also as moisturisers for the skin or the mucosa in cosmetic preparations and pharmaceutical compositions, as agents for maintaining joint mobility and for wound dressings. Cosmetic preparations are, for example, skin-care and hair-care preparations and deodorants. The polymers according to the invention, and especially gels prepared therefrom, are also suitable for the manufacture of compositions having controlled release of active ingredient over a prolonged period, for example pharmaceutical and pesticidal active ingredients or aromatic substances.
In aqueous solutions the water-soluble polymers according to the invention also have a viscosity-increasing and dispersing action and can be used as surfactants and thickeners. They are suitable, for example, as additives in suspensions, emulsions, dispersions and aqueous solutions, for example in the preparation of foodstuffs or biologically active ingredient concentrates and colouring and pigmenting preparations.
The polymers according to the invention can be used in a manner known per se to prepare films and foils that can be used as membranes or as wound dressings; alternatively, capsules for active ingredients or coated active ingredients can be prepared in a manner known per se, the active ingredient being released into the environment in a delayed and continuous manner.
It is also possible for solid carrier materials, for example metals, semimetals, ceramics, glass, metal and semimetal oxides or nitrides, wood, paper and plastics, to be coated with the polymers according to the invention and for those coated materials to be used, for example, as a base material for sensors.
The polymers according to the invention can be used, for example, also in the manufacture of soft contact lenses from corresponding hydrogels or for the manufacture of hard contact lenses having permanently hydrophilic surfaces or for the modification of the surfaces of contact lenses or for the cleaning of contact lenses.
The invention relates also to the use of the water-soluble polymers according to the invention as thickeners and surfactants.
The invention relates also to the use of the polymers according to the invention as a carrier for active ingredients to provide controlled release of the active ingredient.
The invention relates also to the use of the polymers according to the invention for the manufacture, modification or cleaning of contact lenses.
The following Examples illustrate the invention in more detail.
A) Preparation of starting materials
EXAMPLE A1 α, ω-Dicarboxylic acid divinyl esters
The esters are prepared in accordance with the procedure of Swern, D., Jordan, E. F., in Organic Syntheses Coll. Vol. IV, Wiley, New York, 1963, pp 977-980.
Under nitrogen, 2 mol of dicarboxylic acid are suspended in a seven-to eight-fold molar excess of vinyl acetate, and 1 g of Li(PdCl2) is added. The reaction is started by heating and the addition of a few drops of concentrated sulfuric acid. The mixture is stirred for 20 hours under reflux. Then 1 g of sodium acetate and 10 g of activated carbon are added and the solution is filtered and concentrated. The residue is diluted with 400 ml of diethyl ether, extracted with 5×200 ml of a cold-saturated sodium hydrogen carbonate solution and washed with water. The dried ether phase is filtered and concentrated. For purification, the mixture is separated with dichloromethane over a column of silica gel. The average yields are 50 to 90%.
The following are prepared in that manner: 1,4-divinylbutanedioate, 1,6-divinylhexanedioate, 1,12-divinyldodecanedioate, 1,16-divinylhexadecanedioate, 1,22-divinyldocosanedioate, 4,4'-divinylbiphenyldioate.
α,ω-Dicarboxylic acid diisopropenyl esters are prepared in accordance with the procedure of Rothman, E. S., Serota, S., Perlstein, T., Swern, D., J. Org. Chem. 27 (1962), 3123-3127.
B) Preparation of monomers
EXAMPLE B1 γ-Cyclodextrinyl-vinyl-hexadecanedioate
2.5 g of γ-cyclodextrin (1.92 mmol) are dissolved in 60 ml of phosphate buffer (0.1 mol/liter, pH 7.0) and 140 ml of ethanol, and 5.0 g of 1,16-divinylhexadecanedioate (17.5 mmol) are added. The mixture is stirred for 68 hours at 50° C. The solution is then concentrated and made up to 300 ml with water. The mixture is extracted twice using 200 ml of diethyl ether each time and the aqueous phase is lyophilised. The crude product is suspended in 25 ml of water, and 150 ml of acetone are added. After filtration and lyophilisation, 0.68 g (23%) of product is obtained.
EXAMPLE B2 β-Cyclodextrinyl-vinyl-dodecanedioate
5 g of β-cyclodextrin (4.4 mmol) are suspended in 120 ml of phosphate buffer (0.1 mol/liter, pH 7.0) and 280 ml of ethanol, and 10.0 g of divinyldodecanedioate (43.4 mmol) are added. The mixture is stirred for 30 hours at 50° C. The solution is then concentrated and made up to a volume of 200 ml with water. The suspension is washed twice using 200 ml of diethyl ether each time and dried on a lyophiliser. The crude mixture is suspended in 50 ml of water, and 270 ml of acetone are added. After lyophilisation, the filtrate yields 2.4 g of product (40%).
EXAMPLE B3 α-Cyclodextrinyl-vinyl-hexanedioate
50 g of α-cyclodextrin (51 mmol) are dissolved in 3.5 liters of phosphate buffer (0.1 mol/liter, pH 7.0) and 1.5 liters of ethanol, and 50 g of divinylhexanedioate (0.25 mol) are added. The mixture is stirred for 30 hours at 50° C. The solution is then concentrated to 1 liter, filtered and extracted three times using 1 liter of diethyl ether each time. The aqueous phase is lyophilised and the crude product is dissolved in 940 ml of water and reprecipitated with 5.64 liters of acetone. After filtration and concentration to dryness by evaporation, 28.35 g remain which are dissolved in 300 ml of water and stirred with weakly basic anion exchanger (Dowex IRA-93). Lyophilisation of the filtrate yields 17.4 g of product (30%).
1 H-NMR (250 MHz, D2 O): 1.68 ppm (s, broad, 2(-βCH2 -)), 2.43 ppm (s, broad, 2(-αCH2)), 3.33 to 3.95 ppm (cyclodextrin), 4.03 ppm (m, H-3A), 4.92 ppm (s, 5H-1), 5.11 ppm (d, H-1A), 5.24 ppm (m, H-2 A), 7.08 ppm (dt, --HC═CH2).
EXAMPLE B4 β-Cyclodextrinyl-vinyl-hexanedioate
10 g of β-cyclodextrin (7.7 mmol) and 10 g of divinylhexanedioate (50.5 mmol) are suspended in 700 ml of phosphate buffer (0.1 mol/liter, pH 7.0) and 300 ml of ethanol. The solution is heated to 50° C. and stirred for 20 hours and then concentrated to 0.5 liter. After washing three times using 250 ml of diethyl ether each time, the aqueous phase is filtered and lyophilised. The crude mixture is dissolved in 180 ml of water, and 1080 ml of acetone are added. After filtration the solution is concentrated and lyophilised. 6.74 g of product (61%) are obtained.
EXAMPLE B5 α-Cyclodextrinyl-vinyl-butanedioate
1.34 g of α-cyclodextrin (1.37 mmol) are dissolved in 75 ml of phosphate buffer (69 mmol/liter, pH 7.0) and 32 ml of ethanol. After the addition of 2.68 g of divinylbutanedioate (15.75 mmol), the mixture is stirred for 40 hours at 50° C. The mixture is then concentrated to half its volume and adjusted to a volume of 200 ml with water. The solution is washed twice using 200 ml of diethyl ether each time and lyophilised. The crude product is taken up in 32 ml of water, and 192 ml of acetone are added. After filtration and lyophilisation, the substance is dissolved in 68 ml of water and stirred with weakly basic anion exchanger (Amberlite IRA-93). Further filtration and freeze-drying yield 300 mg (20%) of product.
EXAMPLE B6 Maltosylcyclodextrinyl-vinyl-hexanedioate
5 g of maltosylcyclodextrin (3.9 mmol) are dissolved in 350 ml of phosphate buffer (69 mmol/liter, pH 7.0) and 150 ml of ethanol, and 5 g (25 mmol) of divinylhexanedioate are added. After being stirred for 20 hours at 50° C., the mixture is cooled and extracted twice using 250 ml of diethyl ether each time. The aqueous phase is lyophilised and taken up in 91 ml of water. The material that precipitates on the addition of 546 ml of acetone is filtered off and the filtrate is concentrated and dried, 2.2 g of product (39%) are obtained.
EXAMPLES B7 to B13 6-O-glucosyl-vinyl-decanedioate
0.5 g of D-glucose (2.78 mmol), 2.0 g of divinyldecanedioate (7.87 mmol) and 0.5 g of lipase (Humicola lanuginosa) are weighed into a container and suspended in 50 ml of acetone. The mixture is stirred for several days at 50° C., then diluted and filtered. Ethyl acetate is added to the filtrate and the precipitate is separated off. The solvents are evaporated off and the residue is taken up in ethyl acetate and hexane is then added. The supernatant is digested. The product is obtained in the form of a pale yellow oil in a yield of 0.924 g (85%). Purification by silica gel column chromatography with dichloromethane/methanol (5:1) yields 48% product.
1 HNMR (250 MHz, deuterated acetone): 1.20 ppm (s, 8H, γ,γ',δ,δ'--CH2 --), 1.48 ppm(m, 4H, β,β'--CH2 --), 2.19 ppm (t, 2H, α--C2 --), 2.31 ppm (t, 2H, α'--CH2 --), 3.19 ppm (m, 2H, H-4, H-2), 3.57 ppm (t, 1H, H-3), 3.84 ppm (m, 1H, H-5), 4.03 ppm (q, 1H, H-6a), 4.20 ppm (d, 1H, H-6b), 4.47 ppm (d, 1H, --CH═CH2 a), 4.72 ppm (d, 1H, --CH═CH2 b), 4.98 ppm (d, 1H, H-1), 7.17 ppm (dd, 1H, --CH═CH═CH2).
The products listed in the following Table are prepared in analogous manner.
______________________________________                                    
Exam-                                                                     
ple   Saccharide                                                          
                Product              Yield                                
______________________________________                                    
B8    D-mannose 6-O-mannosyl-vinyl-decanedioate                           
                                     85%                                  
B9    maltose   6'-O-maltosyl-vinyl-decanedioate                          
                                     15%                                  
B10   D-ribose  5-O-ribosyl-vinyl-decanedioate                            
                                     37%                                  
B11   β-methyl-                                                      
                6-O-β-methylglucosidyl-vinyl-                        
                                     84%                                  
      glucoside octanedioate                                              
B12   β-octyl-                                                       
                6-O-β-octylglucosidyl-vinyl-                         
                                     76%                                  
      glucoside octanedioate                                              
B13   adenosine 5'-O-adenosyl-vinyl-dodecanedioate                        
                                      4%                                  
______________________________________
C) Preparation of polymers
3.a) Latex polymers
In accordance with the Patent Examples of: Noda, I., U.S. Pat. No. 4,735,843, 5th Apr., 1988. In the Patent, oligooleyl ethoxylate ("Volpo 20", Examples 1, 2, 4, 6) and butadiene/ethylene block copolymers (Example 3) are described as emulsifiers for latex polymerisations. Here they are replaced by mono-functionalised cyclodextrins having emulsifying properties (β-cyclodextrinyl vinyldodecanedioate and γ-cyclodextrinyl vinylhexadecanedioate).
EXAMPLE C1 β-Cyclodextrinyl-vinyl-dodecanedioate/isoprene/styrene latex
Under argon, 120 mg of β-cyclodextrinyl-vinyl-dodecanedioate and 60 mg of potassium peroxodisulfate are weighed into a flask and dissolved in 27 ml of double-distilled water that has been rinsed with argon. 50 μl of dodecylmercaptan, 0.77 ml of styrene and 3.08 ml of isoprene are added thereto. The flask is closed and, with stirring, the reaction is started by heating to 50° C. After 16 hours the latex is obtained in the form of a whitish emulsion.
A transparent, water-resistant and hydrophilic film (contact angle about 45°) is obtained when the latex described according to Example C1 is spread onto a glass surface and dried for 3 days under a current of hot air at 100° C.
EXAMPLES C2 to C13
Under argon, 12 mg of azobis-isobutyronitrile and 200 mg (0.18 mmol) of α-cyclodextrinyl-vinyl adipate are weighed into a 5 ml flask and dissolved in 1 ml of argonised solvent. The comonomer (0.36 mmol) is added dropwise, the flask is closed and the mixture is stirred at 60° C. for from 18 to 36 hours. After cooling, the product is precipitated with ethyl acetate and filtered off. A 10% aqueous solution of the residue is treated with five times the volume of acetone and the precipitate is filtered off and dried, and the yield is determined.
The results can be found in the following Table:
__________________________________________________________________________
                          Cyclo- Cyclodextrin                             
Exam-                Yield                                                
                          dextrin/-                                       
                                 content                                  
ple Comonomer                                                             
            Solvent  (%)  comonomer                                       
                                 (% by wt.)                               
__________________________________________________________________________
C2  acrylamide                                                            
            water/-  55   1/33   28                                       
            methanol (1/1)                                                
C3  NVP.sup.2)                                                            
            water/-  80   1/10   46                                       
            methanol (1/1)                                                
C4  HEMA.sup.3)                                                           
            water/-  75   1/1    77                                       
            methanol (1/1)                                                
C5  butyl   water/-  85   2/1    85                                       
    acrylate                                                              
            methanol (1/1)                                                
C6  butyl   water/-  80   1      86                                       
    acrylate                                                              
            methanol (1/1)                                                
C7  butyl   methanol 65   1/1.7  72                                       
    acrylate                                                              
C8  styrene methanol 72   1      86                                       
C9  MAPS.sup.4)                                                           
            methanol 71   13/1   85                                       
C10 butyl   dimethyl-                                                     
                     61   1/1.5  74                                       
    acrylate                                                              
            formamide                                                     
C11 MAPS.sup.4)                                                           
            dimethyl-                                                     
                     56   14/1   85                                       
            formamide                                                     
C12 styrene dimethyl-                                                     
                     58   1      86                                       
            formamide                                                     
C13.sup.1)                                                                
    isoprene                                                              
            dimethyl-                                                     
                     60   1/2.2  60                                       
            formamide                                                     
__________________________________________________________________________
 .sup.1) cyclodextrinyl-vinyl-dodecanedioate                              
 .sup.2) Nvinylpyrrolidone                                                
 .sup.3) 2hydroxyethyl methacrylate                                       
 .sup.4) 3methacryloxypropylpentamethyldisiloxane
EXAMPLE C14
Under argon, 12 mg of azobis-isobutyronitrile and 200 mg (0.18 mmol) of α-cyclodextrinyl-vinyl adipate are weighed into a 5 ml flask and dissolved in 1 ml of argonised methanol/water (1/1). Hydroxyethyl methacrylate (0.36 mmol) and 10 μl of ethylene glycol bismethacrylate are added and the mixture is stirred at 60° C. for 18 hours. An insoluble, transparent hydrogel is obtained in a yield of 90%.

Claims (39)

I claim:
1. A compound of formula I or Ia
R--Y--CO--R.sub.3 --CO--O--A                               (I),
R--Y--CO--R.sub.3 --CO--O--CH.sub.2 --A.sub.1              (Ia),
wherein
R is a radically polymerizable hydrocarbon group,
R3 is a direct bond, linear or branched C1 -C22 alkylene, C3 -C8 cycloalkylene or C6 -C14 arylene,
A is a radical, reduced by a hydroxy group in a 2- or 3- position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
A1 is a radical, reduced by a hydroxymethyl group of a monomeric or linear or branched oligomeric carbohydrate or of a derivative of such a carbohydrate, and
Y is --O--, --NH--, or --N(C1 -C6 alkyl)--.
2. A compound according to claim 1 wherein R contains from 2 to 12 carbon atoms.
3. A compound according to claim 1 wherein the radical R contains ethene or ethyne groups as radically polymerisable groups.
4. A compound according to claim 1 wherein R is alkenyl, alkynyl, vinylphenyl or vinylbenzyl.
5. A compound according to claim 4 wherein R as alkenyl is vinyl, allyl, 1-propen-2-yl, 1-buten-2- or -3- or -4-yl, 2-buten-3-yl, or an isomer of pentenyl, hexenyl, octenyl, decenyl or dodecenyl.
6. A compound according to claim 4 wherein R as alkynyl is HCC--Cm H2m -- or C1 -C9 alkyl-CC--Cm H2m -- wherein m is an integer from 1 to 10 and the total number of carbon atoms is from 3 to 12.
7. A compound according to claim 6 wherein R is propargyl.
8. A compound according to claim 1 wherein Y is --O--, --NH--, --Nmethyl-- or --Nethyl--.
9. A compound according to claim 8 wherein Y is --O-- or --NH--.
10. A compound according to claim 1 wherein R3 as alkylene contains from 2 to 22 carbon atoms.
11. A compound according to claim 10 wherein R3 as alkylene contains from 2 to 20 carbon atoms.
12. A compound according to claim 11 wherein R3 as alkylene contains from 4 to 18 carbon atoms.
13. A compound according to claim 1 wherein R3 as cycloalkylene contains from 4 to 6 carbon atoms.
14. A compound according to claim 1 wherein R3 as arylene is C6 -C14 arylene.
15. A compound according to claim 14 wherein R3 is 1,2-, 1,3- or 1,4-phenylene, 2,3-, 2,7- or 2,8-naphthylene, or a biphenylene of the formula ##STR5## wherein X is a direct bond, --CH2 --, CH3 CH═, (CH3)2 C═, cyclohexylidene, --O--, --S--, --CO--, --CO2 --, --SO--, --SO2 --, --NH--, --CO--NH--, --N(C1 -C4 alkyl)-- or --CO--N(C1 -C4 alkyl)-.
16. A compound according to claim 1 wherein A as the radical of a cyclic-oligomeric carbohydrate is a cyclodextrin having from 6 to 8 monosaccharide units.
17. A compound according to claim 16 wherein A as the radical of a cyclodextrin or cyclodextrin derivative is derived from α-, β- or γ-cyclodextrin or from 6-methyl-, 6-hydroxyethyl-, 6-hydroxypropyl-, 6-acetyl- or 6-maltosyl-cyclodextrin as cyclodextrin derivative.
18. A compound according to claim 1 wherein A1 as the radical of an oligomeric carbohydrate is derived from an oligosaccharide having from 2 to 10 saccharide units.
19. A compound according to claim 1 wherein A1 as the radical of a mono- or oligo-saccharide is derived from an aldose or ketose.
20. A compound according to claim 1 wherein A1 as the radical of a monosaccharide is derived from an aldopentose, aldohexose, ketopentose or ketohexose.
21. A compound according to claim 1 wherein A1 as the radical of a monosaccharide is derived from D-ribose, D-arabinose, D-xylose or D-lyxose; D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose or D-talose; D-ribulose or D-xylulose; D-psicose, D-fructose, D-sorbose or D-tagatose; as the radical of a disaccharide is derived from trehalose, maltose, isomaltose, cellobiose, gentiobiose, saccharose or lactose; and as the radical of a trisaccharide is derived from raffinose or panose.
22. A compound according to claim 1 wherein A1 as the radical of an oligosaccharide is an oligomeric decomposition product of a polysaccharide.
23. A compound according to claim 1, wherein A1 is the radical of derivatives of monomeric and linear or branched oligomeric carbohydrates, those derivatives are selected from the group consisting of derivatives substituted in the 1-, 2- or 3- positions by C1 -C12 alkyl, C2 -C4 hydroxyalkyl and C1 -C12 acyl; natural nucleosides; synthetic nucleosides; and oligomeric nucleosides including from 2 to 20 nucleosides.
24. A compound according to claim 1 wherein the group R is allyl, propargyl, p-vinylphenyl, p-vinylbenzyl or a radical of the formula R1 CH═CR2 -- wherein R1 is H or C1 -C6 alkyl and R2 is H, C1 -C6 alkyl or phenyl.
25. A compound according to claim 24 wherein R1 as alkyl contains from 1 to 4 carbon atoms.
26. A compound according to claim 25 wherein R1 as alkyl is methyl or ethyl.
27. A compound according to claim 24 wherein R1 is H, methyl or ethyl.
28. A compound according to claim 27 wherein R1 is H.
29. A compound according to claim 24 wherein R2 as alkyl contains from 1 to 4 carbon atoms.
30. A compound according to claim 24 wherein R2 as alkyl is methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl.
31. A compound according to claim 24 wherein R2 is H, methyl, ethyl, propyl or butyl.
32. A compound according to claim 24 wherein R1 is H and R2 is H, methyl, ethyl, n-propyl or n-butyl.
33. A compound according to claim 24 wherein R1 and R2 are each H.
34. A process for the preparation of a compound of formula I or Ia,
R--Y--CO--R.sub.3 --CO--O--A                               (I),
R--Y--CO--R.sub.3 --CO--O--CH.sub.2 --A.sub.1              (Ia),
wherein
R is a radically polymerizable hydrocarbon group,
R3 is a direct bond, linear or branched C1 -C22 alkylene, C3 -C8 cycloalkylene or C6 -C14 arylene,
A is a radical, reduced by a hydroxy group in a 2- or 3- position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
A1 is a radical, reduced by a hydroxymethyl group of a monomeric or linear or branched oligomeric carbohydrate or of a derivative of such a carbohydrate, and
Y is --O--, --NH--, or --N(C1 -C6 alkyl)-,
said process comprising the step of transesterifying a divinyldicarboxylic acid ester of formula II
R.sub.1 CH═CR.sub.2 --O--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1(II),
or a monovinyl ester of formula IIa
R"--Y--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1        (IIa),
with a cyclo-oligomeric carbohydrate of the formula A--OH, or with a derivative thereof, wherein R1 is H or C1 -C6 alkyl, R2 is H, C1 -C6 alkyl or phenyl and R" is a non-vinylic radically polymerizable hydrocarbon group.
35. A process of claim 34, wherein R is a radically polymerizable vinyl ester group, further comprising transesterifying with an alcohol of formula R'--OH, where R' is a non-vinylic radically polymerizable hydrocarbon group.
36. A process of claim 34, wherein R is a radically polymerizable vinyl ester group, further comprising amidating with an amine selected from the group consisting of R'NH2 and R'NHC1 -C4 alkyl, where R' and R", each independently of the other, are non-vinylic radically polymerizable hydrocarbon groups.
37. A process for the preparation of a compound of formula I or Ia,
R--Y--CO--R.sub.3 --CO--O--A                               (I),
R--Y--CO--R.sub.3 --CO--O--CH.sub.2 --A.sub.1              (Ia),
wherein
R is a radically polymerizable hydrocarbon group,
R3 is a direct bond, linear or branched C1 -C22 alkylene, C3 -C8 cycloalkylene or C6 -C14 arylene,
A is a radical, reduced by a hydroxy group in a 2- or 3- position, of a cyclic-oligomeric carbohydrate or of a derivative of such a carbohydrate,
A1 is a radical, reduced by a hydroxymethyl group of a monomeric or linear or branched oligomeric carbohydrate or of a derivative of such a carbohydrate, and
Y is --O--, --NH--, or --N(C1 -C6 alkyl)--
said process comprising the step of transesterifying a divinyldicarboxylic acid ester of formula II
R.sub.1 CH═CR.sub.2 --O--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1(II),
or a monovinyl ester of formula IIa
R"--Y--CO--R.sub.3 --CO--O--R.sub.2 C═CHR.sub.1        (IIa),
in the presence of lipolytic enzymes with a monomeric or linear oligomeric carbohydrate of the formula A1 --CH2 OH, or with a derivative thereof, wherein R1 is H or C1 -C6 alkyl, R2 is H, C1 -C6 alkyl or phenyl and R" is a non-vinylic radically polymerizable hydrocarbon group.
38. A process of claim 37, wherein R is a radically polymerizable vinyl ester group, further comprising transesterifying with an alcohol of formula R'--OH, where R' is a non-vinylic radically polymerizable hydrocarbon group.
39. A process of claim 37, wherein R is a radically polymerizable vinyl ester group, further comprising amidating with an amine selected from the group consisting of R'NH2 and R'NHC1 -C4 alkyl, where R' and R", each independently of the other, are non-vinylic radically polymerizable hydrocarbon groups.
US08/256,828 1992-11-30 1993-11-19 Polymerisable carbohydrate esters, polymers therefrom and their use Expired - Fee Related US5488102A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/467,248 US5571882A (en) 1992-11-30 1995-06-06 Polymersable carbohydrate esters, polymers therefrom and their use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH3655/92 1992-11-28
CH365692 1992-11-30
PCT/EP1993/003236 WO1994012540A1 (en) 1992-11-30 1993-11-19 Polymerizable carbohydrate esters, polymers made from such esters and the use of such polymers

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US08/467,248 Division US5571882A (en) 1992-11-30 1995-06-06 Polymersable carbohydrate esters, polymers therefrom and their use

Publications (1)

Publication Number Publication Date
US5488102A true US5488102A (en) 1996-01-30

Family

ID=4260706

Family Applications (2)

Application Number Title Priority Date Filing Date
US08/256,828 Expired - Fee Related US5488102A (en) 1992-11-30 1993-11-19 Polymerisable carbohydrate esters, polymers therefrom and their use
US08/467,248 Expired - Lifetime US5571882A (en) 1992-11-30 1995-06-06 Polymersable carbohydrate esters, polymers therefrom and their use

Family Applications After (1)

Application Number Title Priority Date Filing Date
US08/467,248 Expired - Lifetime US5571882A (en) 1992-11-30 1995-06-06 Polymersable carbohydrate esters, polymers therefrom and their use

Country Status (15)

Country Link
US (2) US5488102A (en)
EP (1) EP0624166B1 (en)
JP (1) JPH07503757A (en)
AT (1) ATE151778T1 (en)
AU (1) AU683631B2 (en)
CA (1) CA2129108A1 (en)
DE (1) DE59306199D1 (en)
DK (1) DK0624166T3 (en)
ES (1) ES2102186T3 (en)
FI (1) FI943533A7 (en)
GR (1) GR3024014T3 (en)
HK (1) HK1006314A1 (en)
NO (1) NO307342B1 (en)
NZ (1) NZ258533A (en)
WO (1) WO1994012540A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719244A (en) * 1995-06-05 1998-02-17 National Starch And Chemical Investment Holding Corporation Latex binders and coatings containing polymers derived from polymerizable saccharide monomers
US5859217A (en) * 1995-11-27 1999-01-12 Director-General Of Agency Of Industrial Science And Technology Process for producing polymerization sugar esters
US6388047B1 (en) 1999-04-12 2002-05-14 Cornell Research Foundation, Inc. Hydrogel-forming system with hydrophobic and hydrophilic components
US6509323B1 (en) 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
US6716445B2 (en) 1999-04-12 2004-04-06 Cornell Research Foundation, Inc. Hydrogel entrapping therapeutic agent and stent with coating comprising this
US6884789B2 (en) 1998-07-01 2005-04-26 California Institute Of Technology Linear cyclodextrin copolymers
US20070065484A1 (en) * 2005-09-21 2007-03-22 Chudzik Stephen J In situ occlusion using natural biodegradable polysaccharides
US20070065483A1 (en) * 2005-09-21 2007-03-22 Chudzik Stephen J In vivo formed matrices including natural biodegradable polysaccharides and uses thereof
US20080058427A1 (en) * 2002-09-06 2008-03-06 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
US20080154241A1 (en) * 2006-12-07 2008-06-26 Burkstrand Michael J Latent stabilization of bioactive agents releasable from implantable medical articles
US20090280181A1 (en) * 2008-05-07 2009-11-12 Joram Slager Delivery of nucleic acid complexes from particles
US20110237540A1 (en) * 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US8901092B2 (en) 2010-12-29 2014-12-02 Surmodics, Inc. Functionalized polysaccharides for active agent delivery
US11464871B2 (en) 2012-10-02 2022-10-11 Novartis Ag Methods and systems for polymer precipitation and generation of particles

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5618876A (en) * 1995-06-05 1997-04-08 National Starch And Chemical Investment Holding Corporation Latex binders and coatings containing polymers derived from polymerizable saccharide monomers
US5654198A (en) * 1995-06-05 1997-08-05 National Starch And Chemical Investment Holding Corporation Detectable water-treatment polymers and methods for monitoring the concentration thereof
JP4547515B2 (en) * 1999-01-22 2010-09-22 独立行政法人産業技術総合研究所 Nucleoside derivatives, process for producing the same, and nucleoside-containing polymer
US6213604B1 (en) * 1999-05-20 2001-04-10 Bausch & Lomb Incorporated Plasma surface treatment of silicone hydrogel contact lenses with a flexible carbon coating
WO2001002032A1 (en) 1999-06-30 2001-01-11 Novartis Ag Ophthalmic molding
US8469675B2 (en) * 2004-08-26 2013-06-25 Pentair Water Pool And Spa, Inc. Priming protection
US9150666B2 (en) * 2008-01-30 2015-10-06 Ada Foundation Hydrolytically stable, hydrophilic adhesion-promoting monomers and polymers made therefrom
US7955301B1 (en) 2010-01-27 2011-06-07 Warsaw Orthopedic, Inc. Injection shut off valve with pressure actuator for delivery of compositions
US9050274B2 (en) * 2010-01-28 2015-06-09 Warsaw Orthopedic, Inc. Compositions and methods for treating an intervertebral disc using bulking agents or sealing agents
US9486500B2 (en) 2010-01-28 2016-11-08 Warsaw Orthopedic, Inc. Osteoimplant and methods for making
US9125902B2 (en) * 2010-01-28 2015-09-08 Warsaw Orthopedic, Inc. Methods for treating an intervertebral disc using local analgesics
US9511077B2 (en) 2011-04-25 2016-12-06 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for wound healing
US9592243B2 (en) 2011-04-25 2017-03-14 Warsaw Orthopedic, Inc. Medical devices and methods comprising an anabolic agent for treatment of an injury
CN103665255A (en) * 2013-12-06 2014-03-26 东华大学 Method for preparing acrylonitrile-based saccharide-containing copolymer by free radical polymerization
US10080877B2 (en) 2014-07-25 2018-09-25 Warsaw Orthopedic, Inc. Drug delivery device and methods having a drug cartridge
US9775978B2 (en) 2014-07-25 2017-10-03 Warsaw Orthopedic, Inc. Drug delivery device and methods having a retaining member
US10076650B2 (en) 2015-11-23 2018-09-18 Warsaw Orthopedic, Inc. Enhanced stylet for drug depot injector
USD802756S1 (en) 2016-06-23 2017-11-14 Warsaw Orthopedic, Inc. Drug pellet cartridge
US10434261B2 (en) 2016-11-08 2019-10-08 Warsaw Orthopedic, Inc. Drug pellet delivery system and method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1134235A (en) * 1966-05-18 1968-11-20 Milk Marketing Board Improvements relating to carbohydrate-derived polymers
US3565887A (en) * 1968-05-15 1971-02-23 Corn Products Co Unsaturated and long chain esters of cyclodextrin
JPH02184814A (en) * 1989-01-11 1990-07-19 Nippon Fine Chem Co Ltd Water-containing contact lens

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2565887A (en) * 1946-06-21 1951-08-28 Ivers Lee Co Sheathed flexible sheet
JPS645640A (en) * 1987-06-26 1989-01-10 Sintokogio Ltd Method and apparatus for burying lost foam pattern in full mold process

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1134235A (en) * 1966-05-18 1968-11-20 Milk Marketing Board Improvements relating to carbohydrate-derived polymers
US3565887A (en) * 1968-05-15 1971-02-23 Corn Products Co Unsaturated and long chain esters of cyclodextrin
JPH02184814A (en) * 1989-01-11 1990-07-19 Nippon Fine Chem Co Ltd Water-containing contact lens

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Cyclodextrin-Containing Polymers 1 Prep. of Polymers", Harada, Akira, et al., Macromolecules, vol. 9, No. 5, Sep.-Oct. 1976.
"Synthesis of Chemically Modified Cyclodextrins", Croft, Alan, et al. Tetrahedron Report No. 147, Pergamon Press Ltd. 1425-1427.
Cyclodextrin Containing Polymers 1 Prep. of Polymers , Harada, Akira, et al., Macromolecules, vol. 9, No. 5, Sep. Oct. 1976. *
Synthesis of Chemically Modified Cyclodextrins , Croft, Alan, et al. Tetrahedron Report No. 147, Pergamon Press Ltd. 1425 1427. *

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719244A (en) * 1995-06-05 1998-02-17 National Starch And Chemical Investment Holding Corporation Latex binders and coatings containing polymers derived from polymerizable saccharide monomers
US5859217A (en) * 1995-11-27 1999-01-12 Director-General Of Agency Of Industrial Science And Technology Process for producing polymerization sugar esters
US6884789B2 (en) 1998-07-01 2005-04-26 California Institute Of Technology Linear cyclodextrin copolymers
US20110143944A1 (en) * 1998-07-01 2011-06-16 California Institute Of Technology Linear cyclodextrin copolymers
US6509323B1 (en) 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
US20070025952A1 (en) * 1998-07-01 2007-02-01 California Institute Of Technology Linear cyclodextrin copolymers
US7091192B1 (en) 1998-07-01 2006-08-15 California Institute Of Technology Linear cyclodextrin copolymers
US20050129734A1 (en) * 1999-04-12 2005-06-16 Cornell Research Foundation, Inc. Hydrogel entrapping therapeutic agent and stent with coating comprising this
US6388047B1 (en) 1999-04-12 2002-05-14 Cornell Research Foundation, Inc. Hydrogel-forming system with hydrophobic and hydrophilic components
US20040122165A1 (en) * 1999-04-12 2004-06-24 Chee-Youb Won Hydrogel-forming system with hydrophobic and hydrophilic components
US6905700B2 (en) 1999-04-12 2005-06-14 Cornell Research Foundation, Inc. Hydrogel entrapping therapeutic agent and stent with coating comprising this
US6716445B2 (en) 1999-04-12 2004-04-06 Cornell Research Foundation, Inc. Hydrogel entrapping therapeutic agent and stent with coating comprising this
US6916857B2 (en) 1999-04-12 2005-07-12 Cornell Research Foundation, Inc. Hydrogel-forming system with hydrophobic and hydrophilic components
US6709668B2 (en) 1999-04-12 2004-03-23 Cornell Research Foundation, Inc. Hydrogel-forming system with hydrophobic and hydrophilic components
US7138132B2 (en) 1999-04-12 2006-11-21 Cornell Research Foundation, Inc. Hydrogel entrapping therapeutic agent and stent with coating comprising this
US6583219B2 (en) 1999-04-12 2003-06-24 Cornell Research Foundation, Inc. Hydrogel-forming system with hydrophobic and hydrophilic components
US20040151752A1 (en) * 1999-04-12 2004-08-05 Chee-Youb Won Hydrogel entrapping therapeutic agent and stent with coating comprising this
US8580244B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8475781B2 (en) 2002-09-06 2013-07-02 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US9550860B2 (en) 2002-09-06 2017-01-24 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8680202B2 (en) 2002-09-06 2014-03-25 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8609081B2 (en) 2002-09-06 2013-12-17 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8603454B2 (en) 2002-09-06 2013-12-10 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580242B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8110179B2 (en) 2002-09-06 2012-02-07 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8252276B2 (en) 2002-09-06 2012-08-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8314230B2 (en) 2002-09-06 2012-11-20 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8389499B2 (en) 2002-09-06 2013-03-05 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8399431B2 (en) 2002-09-06 2013-03-19 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8404662B2 (en) 2002-09-06 2013-03-26 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US20080058427A1 (en) * 2002-09-06 2008-03-06 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580243B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8518388B2 (en) 2002-09-06 2013-08-27 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US20070065484A1 (en) * 2005-09-21 2007-03-22 Chudzik Stephen J In situ occlusion using natural biodegradable polysaccharides
US20070065483A1 (en) * 2005-09-21 2007-03-22 Chudzik Stephen J In vivo formed matrices including natural biodegradable polysaccharides and uses thereof
US20100226960A1 (en) * 2005-09-21 2010-09-09 Surmodics, Inc. Natural biodegradable matrices and uses thereof
US20080154241A1 (en) * 2006-12-07 2008-06-26 Burkstrand Michael J Latent stabilization of bioactive agents releasable from implantable medical articles
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US9610360B2 (en) 2007-01-24 2017-04-04 Ceruliean Pharma Inc. Polymer drug conjugates with tether groups for controlled drug delivery
US20090280181A1 (en) * 2008-05-07 2009-11-12 Joram Slager Delivery of nucleic acid complexes from particles
US8936811B2 (en) 2008-05-07 2015-01-20 Surmodics, Inc. Device coated with glycogen particles comprising nucleic acid complexes
US20110237540A1 (en) * 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
US8901092B2 (en) 2010-12-29 2014-12-02 Surmodics, Inc. Functionalized polysaccharides for active agent delivery
US11464871B2 (en) 2012-10-02 2022-10-11 Novartis Ag Methods and systems for polymer precipitation and generation of particles

Also Published As

Publication number Publication date
NO942843D0 (en) 1994-07-29
FI943533A0 (en) 1994-07-27
GR3024014T3 (en) 1997-10-31
ATE151778T1 (en) 1997-05-15
DK0624166T3 (en) 1997-10-06
AU5625394A (en) 1994-06-22
EP0624166A1 (en) 1994-11-17
JPH07503757A (en) 1995-04-20
US5571882A (en) 1996-11-05
NO942843L (en) 1994-07-29
NZ258533A (en) 1996-08-27
EP0624166B1 (en) 1997-04-16
WO1994012540A1 (en) 1994-06-09
CA2129108A1 (en) 1994-06-09
DE59306199D1 (en) 1997-05-22
FI943533A7 (en) 1994-07-27
NO307342B1 (en) 2000-03-20
HK1006314A1 (en) 1999-02-19
ES2102186T3 (en) 1997-07-16
AU683631B2 (en) 1997-11-20

Similar Documents

Publication Publication Date Title
US5488102A (en) Polymerisable carbohydrate esters, polymers therefrom and their use
HK1006314B (en) Polymerizable carbohydrate esters, polymers made from such esters and the use of such polymers
US5693768A (en) Unsaturated carbohydrate derivatives polymers thereof and their use
US4868251A (en) Ultraviolet light absorbing silicone compositions
US5164492A (en) Glycoside derivatives, polymers containing glycoside derivatives, process for their preparation and use of said polymers
US5474915A (en) Method of making poly(sugar acrylates) using hydrolytic enzymes
AU699377B2 (en) Poly-unsaturated carbohydrate derivatives, polymers thereof and their use
US4328337A (en) High polymeric compounds having saccharide side chains
EP0897014A2 (en) Method for producing glycoconjugates
EP0668294B1 (en) Unsaturated carbohydrate derivatives, polymers therefrom and their application
JP3477723B2 (en) UV absorber and ultraviolet absorbing composition containing the same
US4465827A (en) Process for preparing high polymeric substance having saccharide side chains
US20080281064A1 (en) Novel Glycopolymers, Uses Thereof, and Monomers Useful for Preparation Thereof
JPH0688066A (en) Ultraviolet absorber and ultraviolet-absorbing composition containing the same
US5173554A (en) Glycoside derivatives, polymers containing glycoside derivatives, process for their preparation, and use of said polymers
JP3217873B2 (en) Benzophenone derivative and ultraviolet absorber containing the same
JP3486909B2 (en) Contact lenses and intraocular lenses
JP3641442B2 (en) Benzophenone derivative and ultraviolet absorber containing the same
CN1162315A (en) Poly-unsaturated carbohydrate derivatives, polymers thereof and their use
US5206318A (en) Styrene derivatives having N-acetylchito-oligosaccharide chains and method for the same
JPH02184814A (en) Water-containing contact lens
EP0394068B1 (en) Styrene derivatives having n-acetylchito-oligosaccharide chains and method for preparing the same
Martin Chemoenzymatic synthesis, characterization and thermodynamic behavior of sugar-containing poly (acrylate) hydrogels

Legal Events

Date Code Title Description
AS Assignment

Owner name: CIBA-GEIGY CORPORATION, NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VETTER, DIRK;REEL/FRAME:007878/0023

Effective date: 19940609

AS Assignment

Owner name: CIBA SPECIALTY CHEMICALS CORPORATION, NEW YORK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CIBA-GEIGY CORPORATION;REEL/FRAME:008454/0062

Effective date: 19961227

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: BIOCURE, INC., GEORGIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CIBA SPECIALTY CHEMICALS CORPORATION;REEL/FRAME:011044/0341

Effective date: 20001010

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 20040130

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362